Preparations of a sulfinyl acetamide

ABSTRACT

The present invention provides processes for the preparation of modafinil which includes the step of reacting benzhydrylthiol and chloroacetamide.

FIELD OF THE INVENTION

The present invention is related to processes for the preparation ofmodafinil from benzhydrol and chloroacetamide.

BACKGROUND OF THE INVENTION

Modafinil, C₁₅H₁₅NO₂S, also known as 2-(benzhydrylsulfinyl) acetamide,or 2-[(diphenylmethyl)sulfinyl]acetamide, is a synthetic acetamidederivative with wake-promoting activity, the structure and synthesis ofwhich has been described in French Patent No. 78 05 510 and in U.S. Pat.No. 4,177,290. Modafinil has been approved by the United States Food andDrug Administration for use in the treatment of excessive daytimesleepiness associated with narcolepsy, and is marketed under the nameProvigil®. Provigil® is a pharmaceutical product comprising tabletscontaining 100 mg or 200 mg of modafinil.

The current invention provides an efficient process that allows forcommercial manufacture of modafinil. The present invention discloses aprocess in which benzhydrylthiol is reacted with chloroacetamide toobtain the corresponding benzhydrylthioacetamide.

A synthesis of modafinil has been described in U.S. Pat. No. 4,177,290,where benzhydrol was reacted with chloroacetic acid.

A related process for synthesizing the levorotatory isomer of modafinilis disclosed in U.S. Pat. No. 4,927,855, issued May 22, 1990.

Processes for synthesizing modafinil derivatives are disclosed in U.S.Pat. No. 4,066,686, issued Jan. 3, 1978; U.S. Pat. No. 4,489,095, issuedDec. 18, 1984; U.S. Pat. No. 5,719,168, issued Feb. 17, 1998; PCTPublication No. 01/15752; and U.S. patent application Ser. No.10/014645.

Processes describing reaction of benzhydryl halides with2-mercaptoacetates were described in U.S. Pat. No. 5,571,825; U.S. Pat.No. 4,964,893; EP Pat. No. 0 528 172; and Chinese Journal of MedicinalChemistry, 1999, 9, 132.

Processes for preparing modafinil have been described in PCT PublicationNo. 02/10125.

The present invention provides an efficient process for the preparationof modafinil, which offers significant commercial advantages whenpreparing modafinil on an industrial scale. The current inventionproduces modafinil with fewer steps and at enhanced yields. Use of thechloroacetamide in the second step of the instant invention directlyadds the desired amide group to the final product in one step. A furtheradvantage of the instant processes is that the four reaction steps canbe conducted in one reaction vessel, without isolation of theintermediates. This reduction in steps and the efficiency of thereaction steps also result in enhanced yields. An additional benefit ofthe present processes is a reduction in the undesirable waste products.

The current processes further provide for significant efficiencies inthe commercial manufacture of modafinil. The overall costs and hazardsof the manufacturing process are reduced, as simpler machinery can beused, less labor is involved and fewer undesirable waste products aregenerated, all of which provides distinct commercial advantages for thepreparation of modafinil on a commercial scale.

SUMMARY OF THE INVENTION

The present invention is directed to processes for the preparation ofmodafinil, which is useful in the treatment of narcolepsy, among otherdisorders. One embodiment of the present invention is the reaction ofbenzhydrylthiol with chloroacetamide to obtain the correspondingbenzhydrylthioacetamide.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides a process of preparingmodafinil comprising the step of reacting chloroacetamide withbenzhydrylthiol to form 2-(benzhydrylthiyl)acetamide. In a furtheraspect of the invention, the benzhydrylthiol is formed by reactingbenzhydrol with thiourea and a suitable acid to form aS-benzhydrylthiouronium salt, followed by reacting theS-benzhydrylthiouronium salt with a suitable base. The reaction stepsmay conducted separately, where each intermediate is independentlyisolated, or the reaction steps are conducted in the same reactionvessel without isolation of any intermediates. A suitable acid can behydrobromic acid, hydrochloric or sulfuric acid. A suitable base can bea metal hydroxide, and in particular, the metal hydroxide can be sodiumhydroxide or potassium hydroxide. Any or all of the reaction steps canbe conducted in a solvent system comprising water and an organic solventselected from tetrahydrofuran, 1,2-dimethoxyethane, MTBE, acetonitrile,chlorobenzene, ortho-dichlorobenzene, or methylcyclohexane. Thetemperature can range from about 25° C. to the refluxing temperature ofthe solvent system, and in particular, the temperature is from about25-75° C.

In a further embodiment, the present invention provides a process ofpreparing modafinil comprising the steps of reacting chloroacetamidewith benzhydrylthiol to form 2-(benzhydrylthiyl)acetamide, and oxidizing2-(benzhydrylthiyl)acetamide.

In an additional embodiment, the present invention provides a process ofpreparing modafinil, comprising:

-   -   (1) reacting benzhydrol with a suitable acid and thiourea to        form a S-benzhydrylthiouronium salt;    -   (2) reacting the S-benzhydrylthiouronium salt with a suitable        base to form benzhydrylthiol;    -   (3) reacting the benzhydrylthiol with chloroacetamide to form        2-(benzhydrylthiyl)acetamide;    -   (4) oxidizing 2-(benzhydrylthiyl)acetamide with a suitable        oxidizing agent to form modafinil.

In certain aspects, the suitable acid is selected from eitherhydrobromic or hydrochloric acid; and the suitable base is selected frompotassium hydroxide or sodium hydroxide; and the process steps areconducted using either a water/tetrahydrofuran or a water/chlorobenzenesolvent system. In other aspects, the process comprises the steps of:

-   -   (1) adding an aqueous 48% hydrobromic acid solution (about 1-10        equivalents) to benzhydrol and thiourea (about 1-10 equivalents)        at a temperature of about 25-75° C., to form        S-benzhydrylthiouronium salt;    -   (2) adding an aqueous solution of potassium hydroxide (about        1-10 equivalents), at a temperature of about 25-75° C., to the        S-benzhydrylthiouronium salt to form the benzhydrylthiol;    -   (3) combining chloroacetamide as either a powder, or in solution        with either water or a water/tetrahydrofuran mixture (about 1-10        equivalents) with the benzhydrylthiol at a temperature of about        25-75° C. to form 2-(benzhydrylthiyl)acetamide.

In an additional aspect, the temperature for steps 1, 2, and 3 is fromabout 50-75° C. In other aspects, the 2-(benzhydrylthiyl)acetamide isoxidized with a suitable oxidizing agent selected fromm-chloroperoxybenzoic acid, sodium periodate, or hydrogen peroxidewherein the hydrogen peroxide may optionally be combined with an acidselected from hydrochloric or acetic acid. In further aspects, a 30%solution of hydrogen peroxide (about 1-2 equivalents) is combined with2-(benzhydrylthiyl)acetamide and acetic acid at a temperature of about25-75° C. to form modafinil. The reaction steps may conductedseparately, where each intermediate is independently isolated, or thereaction steps are conducted in the same reaction vessel withoutisolation of any intermediates.

In another embodiment, the present invention provides for a process ofpreparing modafinil comprising:

-   -   (1) reacting benzhydrol, thiourea (about 1-3 equivalents) and an        aqueous 48% HBr solution (about 1-3 equivalents) in aqueous        tetrahydrofuran at about 70° C. to form S-benzhydrylthiouronium        salt;    -   (2) reacting the S-benzhydrylthiouronium salt with an aqueous        potassium hydroxide solution (about 2-5 equivalents) at about        70° C. to form benzhydrylthiol;    -   (3) reacting chloroacetamide (about 1.05-2 equivalents) in an        aqueous tetrahydrofuran solution, with the benzhydrylthiol at        about 70° C., to form 2-(benzhydrylthiyl)acetamide;    -   (4) reacting the 2-(benzhydrylthiyl)acetamide with acetic acid        (about 2-5 equivalents) and a 30% aqueous hydrogen peroxide        solution (about 1.2-2 equivalents) to form modafinil.

In yet another embodiment, the present invention provides for a processof preparing modafinil comprising:

-   -   (1) reacting benzhydrol, thiourea (about 1-3 equivalents) and an        aqueous 48% HBr solution (about 1-3 equivalents) in aqueous        chlorobenzene at about 70° C. to form S-benzhydrylthiouronium        salt;    -   (2) reacting the S-benzhydrylthiouronium salt with an aqueous        potassium hydroxide solution (about 2-5 equivalents) at about        70° C. to form benzhydrylthiol;    -   (3) reacting chloroacetamide (about 1.05-2 equivalents) in        powder form with the benzhydrylthiol at about 70° C., to form        2-(benzhydrylthiyl)acetamide;    -   (4) reacting the 2-(benzhydrylthiyl)acetamide with acetic acid        (about 2-5. equivalents) and a 30% aqueous hydrogen peroxide        solution (about 1.2-2 equivalents) to form modafinil.

As used herein, the term “about” refers to a range of values from ±10%of a specified value. For example, the phrase “about 50” includes ±10%of 50, or from 45 to 55.

The reactions of the synthetic methods claimed herein are carried out insuitable solvents which may be readily selected by one skilled in theart of organic synthesis, the suitable solvents generally being anysolvent which is substantially nonreactive with the starting materials(reactants), the intermediates, or products at the temperatures at whichthe reactions are carried out, i.e., temperatures which may range fromthe solvent's freezing temperature to the solvent's boiling temperature.A given reaction may be carried out in one solvent or a mixture of morethan one solvent. Depending on the particular reaction, suitablesolvents for a-particular reaction or work-up following the reaction maybe selected. Such suitable solvents, as used herein may include, by wayof example and without limitation, chlorinated solvents, aromaticsolvents, hydrocarbon solvents, ether solvents, polar protic solventsand polar aprotic solvents.

Suitable halogenated solvents include, but are not limited to carbontetrachloride, bromodichloromethane, dibromochloromethane, bromoform,chloroform, bromochloromethane, dibromomethane, butyl chloride,dichloromethane, tetrachloroethylene, trichloroethylene,1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane,2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene,o-dichlorobenzene, chlorobenzene, or fluorobenzene.

Suitable aromatic solvents include, but are not limited to, benzene,toluene, ethylbenzene, xylene, chlorobenzene, dichlorobenzene,trichlorobenzene, nitrobenzene, benzonitrile, anisole, or pyridine.

Suitable hydrocarbon solvents include, but are not limited tocyclohexane, pentane, hexane, cycloheptane, methylcyclohexane, heptane,octane, indane, nonane, and can include the appropriate aromaticsolvents, such as benzene, toluene, ethylbenzene, m-, o-, or p-xylene,etc.

Suitable ether solvents include, but are not limited to diethyl ether,t-butyl methyl ether (“MTBE”), 1,2-dimethoxyethane, 1,3-dioxane,1,4-dioxane, furan, tetrahydrofuran (“THF”), or anisole.

Suitable polar protic solvents include, but are not limited to methanol,ethanol, propanol, butanol, butanol, i-butyl alcohol, t-butyl alcohol,methoxyethanol, ethoxyethanol, pentanol, neo-pentyl alcohol, t-pentylalcohol, cyclohexanol, ethylene glycol, propylene glycol, benzylalcohol, phenol, and glycerol.

Suitable polar aprotic solvents include, but are not limited todimethylformamide (DMF), dimethylacetamide (DMAC),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),formamide, N-methylacetamide, N-methylformamide, acetonitrile,dimethylsulfoxide, propionitrile, ethyl formate, methyl acetate,hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate,isopropyl acetate, t-butyl acetate, sulfolane, N,N-dimethylpropionamide,nitromethane, nitrobenzene, or hexamethylphosphoramide.

Suitable acids include, but are not limited to mineral acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and perchloric acid; organic acids such as formic acid,acetic acid, trifluoroacetic acid, ethanoic acid, propionic acid,methane sulfonic acid, p-toluene sulfonic acid, benzene sulfonic acid,and caproic acid; or Lewis acids, such as boron trifluoride, aluminumchloride, stannic chloride, etc.

Suitable bases include, but are not limited to, inorganic bases such assodium, lithium, and potassium salts of carbonates; sodium, lithium, andpotassium salts of bicarbonates; sodium, lithium and potassiumhydroxides and alkoxides, including tertiary alkoxides, such astert-butoxide; barium, calcium and magnesium hydroxides; ammoniumhydroxide; and organic nitrogen bases, such as tetrabutyl ammoniumhydroxide, pyridine, piperidine, piperazine, morpholine, as well asorganic amines such as methyl amine, dimethyl amine, ethyl amine,diethyl amine, triethyl amine, diisopropyl amine, butyl amine, aniline,benzyl amine, etc.

Suitable oxidizing agents include hydrogen peroxide,m-chloroperoxybenzoic acid (“m-CPBA”), NaIO₄, t-BuOCl, Ca(OCl)₂, NaClO₂,NaOCl, HNO₃, K₂S₂O₈, O₂, acylnitrates, sodium perborate, alkyl- and acylperoxides, such as benzoyl peroxide; and hydroperoxides, such ast-butylhydroperoxide.

The present invention is contemplated to be practiced on at least amultigram scale, kilogram scale, multikilogram scale, or industrialscale. Multigram scale, as used herein, is preferably the scale whereinat least one starting material is present in 10 grams or more, morepreferably at least 50 grams or more, even more preferably at least 100grams or more. Multikilogram scale, as used herein, is intended to meanthe scale wherein more than one kilogram of at least one startingmaterial is used. Industrial scale as used herein is intended to mean ascale which is other than a laboratory scale and which is sufficient tosupply product sufficient for either clinical tests or distribution toconsumers.

The present invention may be further understood by reference to Scheme1, which provides a synthesis for modafinil. The scheme is meant to beillustrative of the present invention, and is not to be taken aslimiting thereof. The synthesis, isolation and purification of modafinilcan be accomplished by methods well known to the skilled artisan oforganic synthesis, and by methods taught herein.

In Step 1, the alcohol group of the benzhydrol is converted into areadily cleavable leaving group, preferably by addition of an acid. Theresultant compound is reacted with thiourea to form the correspondingS-benzhydrylthiouronium salt, wherein the X⁻ is the counterion from thecorresponding acid.

In one embodiment, the benzhydrol is combined with an suitable amount ofthiourea and an suitable acid in a suitable solvent. The benzhydrol canbe combined with the thiourea, followed by addition of the acid, or thethiourea can be combined with the acid, followed by addition of thebenzhydrol. It is desirable to add at least one equivalent of acid toallow the reaction to go to completion. The amount of acid can be fromabout 1 to 10 equivalents, with about 1-3 equivalents being preferred,and about 1.2 equivalents being more preferred. Similarly, it isdesirable to add at least one equivalent of the thiourea to allow thereaction to go to completion. The amount of thiourea can be from about 1to 10 equivalents, with about 1-3 equivalents being preferred, and about1.2 equivalents being more preferred.

The suitable acids are those which allow conversion of the benzhydrol,in the presence of thiourea, to the S-benzhydrylthiouronium salt.Although a large group of acids are acceptable, mineral acids arepreferred, including hydrobromic, hydrochloric and sulfuric acids, withhydrobromic acid being most preferred. Reaction of benzhydrol withhydrobromic acid yields the corresponding S-benzhydrylthiouroniumbromide. Other preferable acids include organic acids, such astrifluoroacetic acid and benzene sulfonic acid.

Suitable solvent systems include water, and mixtures of water withorganic solvents such as ethers, which include diethyl ether,tetrahydrofuran, 1,2-dimethoxyethane, and MTBE; polar organic solventssuch as acetonitrile, methylene chloride, ethyl acetate, acetone; andaromatic solvents, such as benzene, toluene, ethylbenzene, xylene,chlorobenzene, orthodichlorobenzene; and hydrocarbon solvents such ashexane, heptane, methylchlorobenzene, and methylcyclohexane. Preferredsolvents include water/tetrahydrofuran mixtures, water/chlorobenzenemixtures and water/MTBE mixtures.

The reaction temperature can range from room temperature to the refluxof the solvent system. Preferably, the reaction mixture is warmed, fromabout 60-70° C.

The reaction time is one that results in a maximal conversion of thestarting materials to the desired product, and can range from about 1-24h, preferably from about 1-5 h, and more preferably for about 3 h. Thereaction can be monitored by standard methodologies, such as by TLC,HPLC and ¹H NMR analyses. The reaction is considered complete when theanalysis indicates a maximum amount of the desired product in comparisonto the starting materials and by-products.

For example, in Step 1, benzhydrol can be combined with thiourea andabout 48% HBr, and the reaction mixture is heated to about 60-70° C. andstirred until the reaction is complete. The reaction mixture can bedirectly used in the next step without work-up or purification, or thereaction mixture can be cooled to room temperature or placed on an icebath to precipitate S-benzhydrylthiouronium bromide, which can befiltered and washed and purified, if desired, for the next step.

In Steps 2 and 3, the S-benzhydrylthiouronium bromide formed in step 1is converted to the corresponding thiol, and then reacted withchloroacetamide to form 2-(benzhydrylthiyl)acetamide. For example, thethiourea can be converted to the thiol by reaction with a suitable base.The reaction steps 2 and 3 can be carried out in the same reactionvessel as was employed in step 1, without isolation of anyintermediates.

Suitable bases are those that convert the S-benzhydrylthiouronium saltto the corresponding benzhydrylthiol, such as sodium, lithium andpotassium hydroxides and alkoxides, including tertiary alkoxides, suchas tert-butoxide. Other suitable bases include sodium, lithium andpotassium salts of carbonates. Preferred bases are sodium and potassiumhydroxide. The reaction temperature for either step can range from roomtemperature to the reflux temperature of the solvent system. Preferably,the reaction mixture is warmed, from about 60-70° C. The solvent systemcan be the same one used in the previous step, or may additionallyinclude a suitable organic solvent, for example, a polar protic solvent,such as an alcohol, an aromatic solvent or an ether solvent. Alcoholscan include methanol, ethanol, isopropanol, cyclohexanol; aromaticsolvents can include benzene, toluene, chlorobenzene; and ethers caninclude tetrahydrofuran, 1,2-dimethoxyethane and MTBE.

For example, the thiourea can be treated with an aqueous base,preferably NaOH or KOH. The reaction mixture is stirred, typically atroom temperature, until the reaction is complete. The reaction mixtureis typically warmed (typically about 70-80° C.), and chloroacetamide isadded. The chloroacetamide can be added as either a powder, or anaqueous, organic, or partially aqueous solution, with an additionalorganic solvent, such as tetrahydrofuran. It is desirable to add atleast one equivalent of chloroacetamide to allow the reaction to go tocompletion. The amount of chloroacetamide can be from about 1 to 10equivalents, with a slight excess (about 1.05-2.0 mol excess) beingpreferred, and about 1.2 equivalents being more preferred. The reactionmixture is then stirred at the elevated temperature (typically about70-80° C., although in some cases, up to about 100-110° C.) for anappropriate amount of time until the reaction is complete. The reactionmixture can then be cooled, and additional water may be added, and theaqueous layer is separated from the organic layer. The water layer canthen be washed with an suitable organic solvent, and the organicextractions can be combined with the organic layer. The organic portioncan be worked up and a crude product isolated for use in the next step,or it can be directly used in the next step.

In Step 4, the 2-(benzhydrylthiyl)acetamide is oxidized with an suitableoxidizing agent in an suitable solvent to generate modafinil. A suitableoxidizing agent is one which oxidizes the sulfide group of the2-(benzhydrylthiyl)acetamide to the sulfoxide, with minimaloveroxidation to the sulfone. The oxidation step can be carried out inthe same reaction vessel as was employed in the previous steps. Thecorresponding product can be isolated and purified by methods well-knownin the art.

Suitable oxidizing agents can include m-CPBA; sodium periodate; orhydrogen peroxide, benzoyl peroxide, t-butylhydroperoxide, wherein eachperoxide is optionally in combination with a suitable acid. A suitableacid includes carboxylic acids, such as acetic acid, trifluoroaceticacid, benzoic acid, or n-butyric acid; aqueous solutions of an inorganicacid, such hydrochloric, hydrobromic or sulfuric acid; or an appropriateLewis acid. For example, in step 4, acetic acid can be added to thereaction vessel, followed by slow addition of hydrogen peroxide. Theamount of acetic acid can be from about 1 to 10 equivalents, with about2-5 equivalents being preferred, and about 2.5-3.5 equivalents beingmore preferred. It is desirable to add at least one equivalent ofhydrogen peroxide to allow oxidation of the sulfide group in2-(benzhydrylthiyl)acetamide to the corresponding sulfoxide. The amountof hydrogen peroxide can be added with a slight excess (from about 1.2to 2 equivalents), with care taken not to allow overoxidation of thesulfoxide to the corresponding sulfone. Additional solvents canoptionally be added to the reaction mixture if additional solubilizationof the reagents is desired. Such solvents include tetrahydrofuran,methanol or acetone. The reaction temperature can range from roomtemperature to the reflux of the solvent system. Preferably, thereaction mixture is run at room temperature, or with slight warming toabout 50-60° C. Following addition of the hydrogen peroxide, thereaction mixture is stirred until the desired amount of oxidation isobtained. The reaction mixture can be cooled, and may also be quenchedby the addition of a quenching agent, such as bisulfite. Alternatively,m-CPBA can be slowly added to a cooled solution of 2-(benzhydrylthiyl)acetamide (preferably about −15° C. to −25° C.). The reaction mixturecan be stirred at the cool temperature until the reaction is complete,and worked up by conventional techniques.

The product can be isolated by methods well-known in the art, such as byprecipitation, or by extraction. The product can be purified by meanswell-known in the art, such as by recrystallization or chromatography.Typical recrystallization solvents include methanol, and methanol/watersolutions.

It is recognized that the product of the present invention, modafinil,may exist in enantiomeric forms. It is recognized that enantiomers ofpharmaceutical agents may have different biological and pharmacologicalactivity based on the particular configuration of the atoms involved,and that one enantiomer may be more useful in treating a medicinalindication over the other, and conversely. Accordingly, althoughmodafinil is normally prepared as a racemate and can conveniently beused as such, individual enantiomers, (R)-modafinil and (S)-modafinil,can be isolated by conventional techniques if so desired. The racemateof modafinil, individual R— and S-enantiomers and mixtures thereof formpart of the present invention.

It is well known in the art how to isolate optically active enantiomers.The specific enantiomers of modafinil can be resolved from a racemicmixture and recovered by techniques known in the art, such as resolutionof racemic forms, normal, reverse-phase, and chiral chromatography.Direct separation of enantiomers by chromatography, especially liquidchromatography, is widely used. Industrial methods for the preparationof pure enantiomers constitute the resolution of racemates by methodssuch as: direct preferential crystallization, crystallization of thedistereomeric salts, kinetic resolution, enzymatic resolution, anddifferential absorption. For example, two enantiomers may be separatedby diastereomer crystallization, which generally involves reaction ofthe racemate with an optically pure acid or base (the resolving agent)to form a mixture of diastereomeric salts, which subsequently areseparated by crystallization. Diastereomeric crystallization is widelyused on industrial scale using a resolving agent, for example, camphorsulphonic acid, tartaric acid, maleic acid, mandelic acid, phenoxypropionic acid, hydratopic acid, brucine, quinine, ephedrine,.alpha.-methylbenzylamine, amphetamine, deoxyehedrine, and N-methylD-glucamine, etc. Once separated by, for example, fractionalcrystallization, or more commonly, chromatography, the diastereomers arere-converted back into the corresponding enantiomers, which are nowoptically pure. Useful methods of resolving and recovering specificstereoisomers described in Eliel, E. L.; Wilen, S. H. Stereochemistry ofOrganic Compounds; Wiley: New York, 1994, and Jacques, J, et al.Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, eachincorporated by reference herein in their entireties.

EXAMPLES

The following examples are meant to be illustrative of the presentinvention. These examples are presented to exemplify the invention, andare not intended, nor are they to be construed, to limit the scope ofthe invention.

Example 1

To a suspension of benzhydrol (35.00 g, 0.188 mol, 1 equivalent) andthiourea (17.40 g, 0.226 mol, 1.20 equivalents) in tetrahydrofuran/water(35.5 ml/52.5 ml), was added an aqueous 48% HBr solution (25.3 ml, 0.226mol, 1.2 equivalents) over a 10 min period. During the addition, thereaction mixture is heated to 70° C. After 3 h stirring at 70° C., theuronium intermediate was hydrolyzed by addition of an aqueous 9.3Npotassium hydroxide solution (58 ml, 0.542 mol, 2.88 equivalents) over a55 min period. After 1.5 h stirring at 70° C., chloroacetamide (26.6 g,0.282 mol, 1.5 equivalents) in a tetrahydrofuran/water (80 ml/79 ml)solution was added over 15 min. After 1 h stirring at 70° C., thereaction mixture was cooled down to 55° C. and the stirring was stopped.The lower aqueous phase was removed, and the reaction mixture was againstirred. Acetic acid (34.7 ml, 0.601 mol, 3.2 equivalents) was added.Hydrogen peroxide 30% (38.4 ml, 0.376 mol, 2 equivalents) was slowlyadded over 30 min. After 1 h stirring, the reaction mixture was cooledto 20° C. and water (263 ml) was added. The resultant suspension wasstirred at 0° C. overnight. The suspension was then filtered and thesolid was washed with water, and dried to yield modafinil (47.9 g,80.4%). The crude modafinil was purified by recrystallization inmethanol.

Example 2

A suspension of benzhydrol (200.00 g, 1.075 mol, 1 equivalent) andthiourea (99.4 g, 1.293 mol, 1.20 equivalents) inmonochlorobenzene/water (477 ml/300.5 ml) was heated at 70° C. Anaqueous 48% HBr solution (145 ml, 1.29 mol, 1.2 equivalents) was thenadded over a 5 min period. After 3 h stirring at 70° C., the uroniumintermediate was hydrolyzed by addition of an aqueous 9.3N potassiumhydroxide solution (321.7 ml, 2.825 mol, 2.63 equivalents) over a 50 minperiod. After 1.5 h stirring at 70° C., chloroacetamide (152.3 g, 1.612mol, 1.5 equivalents) in powder form was added for over a 15 min period.After 30 min stirring at 70° C., the reaction mixture was cooled down to55° C. and the stirring was stopped. The lower aqueous phase wasremoved, and water (600 ml) was added to the reactor. The reactionmixture was again stirred for 45 min. The lower aqueous phase was thenremoved. Acetic acid (173.3 ml, 3.000 mol, 2.79 equivalents) was added.Hydrogen peroxide 30% (175.4 ml, 1.718 mol, 1.6 equivalents) was slowlyadded for 80 min. After 50 minutes of stirring at 55° C., the reactionmixture was quenched with an aqueous sodium bisulfite solution (275 g).The lower aqueous phase was removed and the reaction mixture was cooled0-5° C. Monochlorobenzene (386 g) was added to dilute the reactionmixture. The resultant suspension was then filtered, and the solid waswashed with water and monochlorobenzene, and dried to yield modafinil(216.7 g, global yield 69.3%, strength 93.9 wt. %). The crude modafinilwas purified by recrystallization in methanol.

As those skilled in the art will appreciate, numerous changes andmodifications may be made to the embodiments of the invention withoutdeparting from the spirit of the invention. It is intended that all suchvariations fall within the scope of the invention.

1. A process of preparing modafinil comprising the step of reactingchloroacetamide with benzhydrylthiol to form2-(benzhydrylthiyl)acetamide.
 2. A process of preparing modafinilcomprising the steps of reacting chloroacetamide with benzhydrylthiol toform 2-(benzhydrylthiyl)acetamide, and oxidizing2-(benzhydrylthiyl)acetamide.
 3. The process of claim 1, wherein thebenzhydrylthiol is formed by reacting benzhydrol with thiourea and asuitable acid to form a S-benzhydrylthiouronium salt, followed byreacting the S-benzhydrylthiouronium salt with a suitable base.
 4. Theprocess of claim 3, wherein the steps are conducted in the same reactionvessel without isolation of any intermediates.
 5. The process of claim3, wherein the suitable base is a metal hydroxide.
 6. The process ofclaim 5, wherein the metal hydroxide is sodium hydroxide or potassiumhydroxide.
 7. The process of claim 3, wherein the suitable acid ishydrobromic acid, hydrochloric or sulfuric acid.
 8. The process of claim3, wherein the reactions are conducted in a solvent system comprisingwater and an organic solvent selected from tetrahydrofuran,1,2-dimethoxyethane, MTBE, acetonitrile, chlorobenzene,ortho-dichlorobenzene, or methylcyclohexane.
 9. The process of claim 8,wherein the temperature is from about 25° C. to the refluxingtemperature of the solvent system.
 10. The process of claim 9, whereinthe temperature is from about 25-75° C.
 11. A process of preparingmodafinil, comprising: (1) reacting benzhydrol with a suitable acid andthiourea to form a S-benzhydrylthiouronium salt; (2) reacting theS-benzhydrylthiouronium salt with a suitable base to formbenzhydrylthiol; (3) reacting the benzhydrylthiol with chloroacetamideto form 2-(benzhydrylthiyl)acetamide; (4) oxidizing2-(benzhydrylthiyl)acetamide with a suitable oxidizing agent to formmodafinil.
 12. The process of claim 11, wherein the suitable acid isselected from either hydrobromic or hydrochloric acid; and the suitablebase is selected from potassium hydroxide or sodium hydroxide; and theprocess steps are conducted using either a water/tetrahydrofuran or awater/chlorobenzene solvent system.
 13. The process of claim 11,wherein: (1) an aqueous 48% hydrobromic acid solution (about 1-10equivalents) is added to benzhydrol and thiourea (about 1-10equivalents) at a temperature of about 25-75° C., to formS-benzhydrylthiouronium salt; (2) an aqueous solution of potassiumhydroxide (about 1-10 equivalents) is added, at a temperature of about25-75° C., to the S-benzhydrylthiouronium salt to form thebenzhydrylthiol; (3) chloroacetamide as either a powder, or in solutionwith either water or a water/tetrahydrofuran mixture (about 1-10equivalents) is combined with the benzhydrylthiol at a temperature ofabout 25-75° C. to form 2-(benzhydrylthiyl)acetamide.
 14. The process ofclaim 11, wherein the temperature for steps 1, 2, and 3 is from about50-75° C.
 15. The process of claim 11, wherein the2-(benzhydrylthiyl)acetamide is oxidized with an oxidizing agentselected from m-chloroperoxybenzoic acid, sodium periodate, or hydrogenperoxide wherein the hydrogen peroxide may optionally be combined withan acid selected from hydrochloric or acetic acid.
 16. The process ofclaim 15, wherein a 30% solution of hydrogen peroxide (about 1-2equivalents) is combined with 2-(benzhydrylthiyl)acetamide and aceticacid at a temperature of about 25-75° C.
 17. The process of claim 16,wherein the preparation of modafinil is conducted in the same reactionchamber without isolation of any intermediates. 18-27. (canceled)